Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy

Introduction IgA nephropathyis a chronic renal disease characterized by mesangial immunodeposits that contain autoantigen, which is aberrantly glycosylated IgA1 with some hinge-region O -glycans deficient in galactose. Macroscopic hematuriaduring an upper respiratory tract infectionis common among patients with IgA nephropathy, which suggests a connection between inflammation and disease activity. Interleukin-6 (IL-6) is an inflammatory cytokine involved in IgA immune response. We previously showed that IL-6 selectively increases production of galactose-deficient IgA1 in IgA1-secreting cells from patients with IgA nephropathy. Methods We characterized IL-6 signaling pathways involved in the overproductionof galactose-deficient IgA1. To understand molecular mechanisms, IL-6 signaling was analyzed by kinomicactivity profiling and Western blotting, followed by confirmation assays using siRNA knock-down and small-molecule inhibitors. Results STAT3was differentially activated by IL-6 in IgA1-secreting cells from patients with IgA nephropathycompared with those from healthy control subjects. Specifically, IL-6 induced enhanced and prolonged phosphorylation of STAT3in the cells from patients with IgA nephropathy, which resulted in overproductionof galactose-deficient IgA1. This IL-6−mediated overproductionof galactose-deficient IgA1 could be blocked by small molecule inhibitors of JAK/STAT signaling. Discussion Our results revealed that IL-6−induced aberrant activation of STAT3-mediated overproductionof galactose-deficient IgA1. STAT3signaling pathway may thus represent a new target for disease-specific therapy of IgA nephropathy.